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3028PHM Human Pharm II > Cancer biology and Chemotherapy > Flashcards

Cancer biology and Chemotherapy Flashcards

1
Q

Summarise the common adverse effect of myelosuppression seen with chemotherapy

A

Myelosupression occurs in chemo and refers to suppress of bone cells, mainly RBC and WBC

Suppression/destruction of RBC = will cause anaemia and severe fatigue

Suppression/destruction of WBC = weaken the immune system, inc the risk of infections

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1
Q

What chemo drug is known for causing cardiac toxicity?

A

Doxorubicin

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2
Q

What chemo drug is known for causing renal toxicity?

A

Cisplatin

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3
Q

What chemo drug is known for causing pulmonary toxicity?

A

bleomycin

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4
Q

What chemo drug is known for causing neurotoxicity?

A

Vincristine

Paclitaxel

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5
Q

List the cancer drugs that are DNA synthesis inhibitors

A

Folate antagonists = methotrexate, pemetrexed

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6
Q

What is the MOA of methotrexate?

A

Inhibit DNA synthesis due to inhibition of dihydrofolate –> prevent conversion to tetrahydropholate –> prevent IMP formation and thus no DNA synth

Reduce toxicity with folinic acid supplementation

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7
Q

What is the MOA of Pemetrexed?

A

Inhibit DHFR, tymidylate synthase and glycinamide ribonucleotide formyltransferase (GRAFT) –> prevents DNA synth

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8
Q

Why are DNA synthesis inhibitor chemo drugs delivered intrathecally?

A

Do not penetrate CNS

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9
Q

What unique cancer can methotrexate be used in?

A

Trophoblastic tumours

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10
Q

What are some notable ADRs of DNA synthesis inhibitor chemo drugs?

A

Myelosuppression = think WBC and RBC

Stomatitis and renal tox (methotrexate)

Hepatotox

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11
Q

List the purine analogue chemo drugs

A

Mecaptopurine = hypoxanthine analogue

Thioguanine = guanine analogue

Used in blood cancers

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12
Q

What is the MOA of purine analogue chemo drugs?

A

Interfere with DNA synthesis due to inhibition of the biosynthesis of adenine and guanine

Prevent creation of functioning base pairs

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13
Q

What are some notable ADRs with purine anaologues?

A

thioguanine = produces dose limiting myelosuppression

Mercaptopurine = causes hepatotoxicity

Both drugs contribute to secondary cancer formation

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14
Q

List the halogenated purine analogues used in chemo

A

FLudarabine

Cladribine

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15
Q

What is the MOA of halogenated purine analogue chemo drugs?

A

Pretend to be DNA

Incorporated into nascent DNA –> cause DNA chain termination

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16
Q

What unique cancer does cladribine treat?

A

hairy cell leukaemia

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17
Q

What types of cancers are commonly treated with fludarabine?

A

blood cancers

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18
Q

List the relevant pyrimidine antagonist drugs used in cancer treatment

A

Cytarabine (cytosine arabinoside) = composed of cytosine and arabinose sugar
- Iv or Subcut

Fluorouracil = analogue of thymine
- IV = solid cancers
- Topical = non-invasive skin cancers

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19
Q

What is the MOA of cytarabine?

A

Active metabolites of cytarabine block DNA synthesis

- inhibition of DNA polymerase 
- Incorporation of drug into nascent DNA --> cause DNA chain termination
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20
Q

What is the MOA of fluorouracil?

A

Has two active metabolites:

- 5-fluorodeoxyuridine monophosphate (5-FdUMP) --> inhibit thymidylate synthetase --> prevent DNA building block thymidine synthesis 

- 5-fluorodeoxyuridine triphosphate (5-FdUTP) ---> incorporated into RNA by RNA polymerase --> interfere with RNA function
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21
Q

What genetic material does 5-FdUMP target?

A

DNA

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22
Q

What genetic material does 5-FdUTP target?

A

RNA

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23
Q

Describe the rationale behind the combination of fluorouracil and leucovorin

A

Synergism happens

Allows 5-FdUMP to bind to thymidylate synthase more efficiently –> inc the ability to drop thymidine

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24
Q

What route of administration causes greatest myelosuppression w/ fluorouracil?

A

More problematic after bolus injection (push-injection)

Mucosal damage is dose limiting with continuous infusion

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25
Q

What is the name of the pyrimidine antagonist which is a cell cycle specific drug?

A

Gemcitabine –> used as first line in pancreatic cancers

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26
Q

What is the MOA of gemcitabine?

A

gemcitabine –> converted to gemcitabine diphosphate and triphosphate –> inhibiting DNA synthesis in the S-phase

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27
Q

List the sub-class of DNA alkylating drugs and the relevant drugs within this (sub)-class

A

Subclass = nitrogen mustards

cyclophosphamide

Ifosfamide

Chlorambucil

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28
Q

Generally explain the MOA of DNA Alkylating drugs

A

Cross-linking DNA strands by forming covalent bonds between alkyl groups of the drug and guanine bases of DNA —> preventing uncoiling of the DNA

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29
Q

When is nausea worse with cyclophosphamide?

A

mild with orally

Severe when given IV

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30
Q

What are some notable ADRs of DNA alkylating drugs?

A

Haemorrhagic cystitis = due to depletion of thiol groups

Cyclophosphamide = dose-limiting myelosuppression

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31
Q

What is the MOA of Platinum compounds used in cancer treatment?

A

Form intrastrand and interstrand covalent bonds with DNA bases –> cross-link DNA

32
Q

What can be used to counter the haemorrhagic cystitis seen predominantly with cyclophosphamide?

A

Administer mesna –> replenish thiol groups and prevent haemorrhagic cystitis

33
Q

What are some notable ADRs of platinum compounds?

A

mild myelosuppression

Severe nausea

Nephrotoxicity

Vomiting

34
Q

What is mitomycin C and what is its MOA?

A

Antineoplastic abs

MOA = alkylates DNA –> strand breakage –> inhibition of DNA synthesis

35
Q

What is mitomycin commonly used for

A

Used along vincristine as salvage therapy for breast cancer

36
Q

List the relevant DNA intercalating drugs

A

Anthracycline = Daunorubicin, Doxorubicin

bleomycin

dactinomycin

37
Q

What are the MOAs of DNA intercalating drugs?

A

1) intercalation of DNA –> inserts self between DNA strands –> prevents DNA synthesis

2) Inhibits topoisomerase (I, II) –> allows DNA to break during replication –> impaired DNA synthesis

3) Formation of free radicals

*Not absorbed into CNS

38
Q

What are some notable ADRs of DNA intercalating drugs?

A

Dose limiting = myelosuppression and cardiac damage

mucosal ulceration, tumour lysis syndrome

IV = severe localised ulceration and necrosis

39
Q

What is the relationship between PEG liposomal doxorubicin and cardiac toxicity?

A

Normally = Doxorubicin accumulates in cardiomyocytes –> inc ROS in the mitocondria –> cardiac toxicity –> dec LVEF

PEG liposomal doxorubicin allows for more tissue specific targeting of doxorubicin into cancerous tissues –> more drug will enter cancer cells –> less drug entering healthy cells –> dec in cardiotoxic effects –> lesser impact on LVEF

40
Q

What is the MOA of bleomycin?

A

Causes DNA intercalation during the G2 phase of cell replication

Also causes iron-catalysed free radical formation and DNA strand breakage

41
Q

What are some notable ADRs of bleomycin?

A

Pulmonary = interstitial fibrosis, hypoxia, death

Mucocutaneous reactions = lack of aminohydralase in skin –> unable to breakdown drug –> drug accumulates in skin (mild stomatitis, skin hyperpigmentation, erythema

42
Q

List the relevant mitotic inhibitor chemo drugs

A

Vinca alkaloids = vincristine, vinblastine

IV only, neither enter CNS

Taxanes = paclitaxel and docetaxel

43
Q

What is the MOA of the Vinca Alkaloids?

A

Inhibit the assembly of microtubules –> prevent cell division and tumour growth

44
Q

What are some notable ADRs of vinca alkaloids?

A

Vincristine = dose-limiting neurotox –> peripheral neuropathy (suppression of deep tendon reflexes, parethesias

- hoarseness in voice, facial palsies, jaw pain

Vinblastine = myelosuppression (dose-limiting) –> little neurotoxicity

45
Q

What is the MOA of taxanes?

A

Block microtubule disassembly –> prevent replication/synthesis of new cells

46
Q

What types of cancers do paclitaxel and docetaxel treat?

A

Docetaxel = castrate resistance prostate cancer (hormone independent cancer)

Paclitxel =metastatic ovarian and breast cancer

47
Q

What are some notable ADRs of taxanes?

A

dose-limiting myelosuppression

Hypersensitivity reactions –> solubility issues

48
Q

What is the function of topoisomerase I and II?

A

Topoisomerase I = breaks and reseals single stranded DNA

Topoisomerase II = breaks and reseals in double-stranded DNA

49
Q

Generally, what do topoisomerase inhibitors do?

A

Cause permanent strand breaks by inhibiting the resealing of nicked strands of DNA

50
Q

List the relevant topoisomerase inhibitors and its MOA

A

Podophyllotoxins (etoposide) = inhibit topoisomerase II

Camptothecin = inhibit topoisomerase I

MOA = inhibition of both topoisomerase -> causing DNA/RNA damage –> prevent further replication –> DNA and cell synthesis

51
Q

What class of drugs do topoisomerase inhibitors have a synergistic relationship with?

A

platinum compounds

52
Q

List the relevant topoisomerase inhibitors

A

Camptothecin analogues = irinotecan (biliary excretion) and topotecan (renal excretion)

Podphyllotoxins = etoposide

53
Q

How is irinotecan metabolised?

A

Rapidly metabolised to active metabolite called SN-38 –> greater anti-tumour activity

SN-38 excreted primarily by bile

54
Q

What is irinotecan commonly used to treat?

A

colorectal cancer that has recurred or progressed following fluorouracil therapy

55
Q

What are some notable ADRs of camptothecin analogues?

A

Both topotecan and irinotecan = dose limiting myelosuppression

Irinotecan produces diarrhoea

56
Q

List the relevant targeted drugs that inhibit protein kinases

A

Imatinib

Dasatinib

Nilotinib

57
Q

What is the MOA of protein kinase inhibitor (imatinib) targeted drugs?

A

Inhibit BCR-ABL tyrosine kinase –> inhibit serine-threonine kinase –> dec malignant transformation and proliferation and inc apoptosis

58
Q

Which protein kinase inhibitors target EGFR?

A

Erlotinib

59
Q

What is the MOA of erlotinib?

A

Protein kinase inhibitor that inhibits EGFR

Dec cell proliferation, inc apoptosis, dec invasion and metastasis, dec angiogenesis

Causing inc cell destruction, slowing cancer cell proliferation

Cetuximab, panitumumab = have same MOA

60
Q

What is the MOA of venetoclax?

A

Inhibit BCL-2 –> promotes apoptosis –> activates caspases –> cancer cell death

61
Q

What is the MOA of sunitinib?

A

Inhibits VEGFR –> inhibits angiogenesis

Bevacizumab works the same

62
Q

What is the MOA of rituximab?

A

Binds CD20 antigen on non-Hodgkin lymphoma cancer –> reduce/impair early cell cycle initiation

63
Q

What is the MOA of trastuzumab?

A

recombinant human mab binds to epidermal growth factor-2 (HER2/neu)[tyrosine kinase] –> inhibit cell proliferation

64
Q

What is the MOA of Ipilimumab?

A

Antibody that binds CTLA-4 –> preventing release of T cell inhibitory signalling –> T cell activation

65
Q

What are some notable ADRs of ipilimumab (yervoy)?

A

Severe/fatal immune mediated ADR = stop drug indefinitely and commence on high dose corticosteroid therapy

Colitis

Hepatitis

Dermatitis

Neuropathies

66
Q

What is the MOA of pembrolizumab? ADRs?

A

mab –> bind PD-1 receptor –> block interaction between PD-1 and ligands (PD-L1 and PD-L2)

ADR = colitis, pneumonitis, hepatitis, hypophysitis –> stop tx

67
Q

What is the MOA of abemaciclib?

A

CDK 4/6 inhibitor –> interfere w/ cell cycle progression –> halt cancer progression of Her+ve/Her2-ve breast cancer

68
Q

What is the MOA and ADR of trodelvy?

A

Sacituzumab govitecan-hziy

Trop2-directed antibody and topoisomerase inhibitor conjugate

ADR = Neutropenia, diarrhoea, N/V

Inc ADR risk w/ reduced UGT1A1 activity

69
Q

What is the role of tamoxifen in cancer treatment?

A

Oestrogen antagonist on breasts –> allow shrinkage of tumour

70
Q

What is the role of aromatase inhibitors (anastrazole and letrozole) in cancer treatment?

A

Prevent oestrogen synth –> useful in hormone dependent breast cancer

71
Q

What is an example of a GnRH agonist? What is the MOA of this group?

A

Leuprorelin

MOA = inc GnRH stimulation which acts on the pituitary –> inc LH on testes –> inc testosterone release –> excessive hormone production –> negative feedback loop of hypothalamus and pituitary –> eventual dec in tumour size/growth due to dec testosterone

72
Q

What is an example of a GnRH antagonist? What is the MOA of this group?

A

Degarelix

MOA = Inhibit GnRH –> inhibits release of LH –> no LH effect on testes —> dec testosterone production –> less testosterone action on testes –> hormone sensitive prostate cancer dec

73
Q

What is an example of an androgen antagonist? What is the MOA of this group?

A

Flutamide, bicalutamide

MOA = prevent the action of dihydrotestosterone by competitively binding to the androgen receptor and inhibiting the binding of DHT —> inhibition of cell proliferation/DNA replication due to lack of testosterone

74
Q

What is the MOA of ketoconazole and abiraterone in prostate cancer?

A

1) inhibit biosynthesis of testosterone

2) Inhibit androstenedione (has role in synth of oestrogen and testosterone) and DHEA DHEAs –> inhibit testosterone release –> reduced cell proliferation

75
Q

What is an example of 5alpha-reductase inhibitor? What is the MOA of this group?

A

Finasteride, dutasteride

MOA = inhibit the conversion of testosterone to potent dihydrotestosterone –> slows growth of testosterone dependent prostate cancers

76
Q

What are some ADRs of androgen-deprivation therapy?

A

Sexual = genital shrinkage, erectile dysfunction, libido loss

Physical = weight gain, gyno, muscle atrophy

Metabolic = osteoporosis, anaemia, HTN, heart disease, diabetes

Emotional/cognitive

Systemic = fatigue

TUmour “flare” = GnRH agonist –> tumour will worsen initally like GnRH agonist –> tumour will shrink/sx improve

77
Q

Explain the direct action of radiotherapy

A

Ionised radiation –> DNA damage –> cells apoptose and die

78
Q

Explain the indirect damage of radiotherapy

A

Ionised radiation –> inc free radical production –> DNA damage –> inc cytokine production –> cell death

3028PHM Human Pharm II (17 decks)

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